Is FA2H p.Phe265Cys (c.794T>G) pathogenic?

FA2H p.Phe265Cys (c.794T>G) is classified Uncertain significance in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: likely pathogenic (0.7081); Ultra-rare (popmax 0.0692%, eas); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Phe265Cys (c.794T>G)?

FA2H p.Phe265Cys (c.794T>G) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Phe265Cys (c.794T>G) in the general population?

FA2H p.Phe265Cys (c.794T>G) is ultra-rare (popmax 0.0692%, eas) (gnomAD).

What do computational predictors say about FA2H p.Phe265Cys (c.794T>G)?

AlphaMissense predicts likely pathogenic (score 0.7081) — an in-silico prediction, not a clinical call.

FA2H p.Phe265Cys

c.794T>G · rs149133141 · VCV1355795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7081 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.7081	likely pathogenic
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0692% East Asian · 29/41,900 alleles

Filtering AF 0.0494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0428%

Overall 0.0025% 39/1,561,580 alleles · ultra-rare exomes 35/1,409,516 · genomes 4/152,064 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0692%	1,445
Remaining individualsnot grpmax-eligible	0.00659%	15,166
South Asian	0.00467%	21,425
European (non-Finnish)	0.000173%	577,201

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FA2H
Protein: p.Phe265Cys
Coding: c.794T>G
MANE Select: NM_024306
dbSNP: rs149133141
Type: single nucleotide variant
Location: chr16:74716592 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 265: the fatty acid hydroxylase domain

Full FA2H gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FA2H p.Phe265= Uncertain significance ★★ same residue
FA2H c.506+1G>C Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269His Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Met1Val Pathogenic ★★ same condition
FA2H p.Pro44Gln Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Pro44Ser Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269Cys Uncertain significance ★★ ⚠ same condition
FA2H p.Glu365Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fa2h-p-phe265cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown